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Article ; Online: Phenotypic differences in intermediate generalized junctional epidermolysis bullosa with homozygous LAMC2 mutation and a potential genetic modifier.

Cowan, Timothy L / Sundberg, John P / Roopenian, Derry C / Sproule, Thomas J / Murrell, Dédée F

Journal of the European Academy of Dermatology and Venereology : JEADV

2024

Language	English
Publishing date	2024-02-20
Publishing country	England
Document type	Letter
ZDB-ID	1128828-0
ISSN	1468-3083 ; 0926-9959
ISSN (online)	1468-3083
ISSN	0926-9959
DOI	10.1111/jdv.19859
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice.

Sproule, Thomas J / Philip, Vivek M / Chaudhry, Nabig A / Roopenian, Derry C / Sundberg, John P

PloS one

2023 Volume 18, Issue 7, Page(s) e0288263

Abstract: Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian ...

Abstract	Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
MeSH term(s)	Animals ; Mice ; Epidermolysis Bullosa, Junctional ; Skin ; Blister ; Epidermis ; Quantitative Trait Loci/genetics
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0288263
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Transcriptome analysis reveals organ-specific effects of 2-deoxyglucose treatment in healthy mice.

Wells, Ann E / Wilson, John J / Heuer, Sarah E / Sears, John D / Wei, Jian / Pandey, Raghav / Costa, Mauro W / Kaczorowski, Catherine C / Roopenian, Derry C / Chang, Chih-Hao / Carter, Gregory W

PloS one

2024 Volume 19, Issue 3, Page(s) e0299595

Abstract: Objective: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic ... ...

Abstract	Objective: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. Methods: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. Results: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. Conclusions: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
MeSH term(s)	Mice ; Animals ; Deoxyglucose/pharmacology ; Deoxyglucose/metabolism ; Mice, Inbred C57BL ; Glucose/metabolism ; Epilepsy ; Gene Expression Profiling
Chemical Substances	Deoxyglucose (9G2MP84A8W) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2024-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0299595
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Article ; Online: Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorum

Thomas J. Sproule / Robert Y. Wilpan / John J. Wilson / Benjamin E. Low / Yudai Kabata / Tatsuo Ushiki / Riichiro Abe / Michael V. Wiles / Derry C. Roopenian / John P. Sundberg

PLoS ONE, Vol 18, Iss

2023 Volume 10

Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment.

Wilson, John J / Wei, Jian / Daamen, Andrea R / Sears, John D / Bechtel, Elaine / Mayberry, Colleen L / Stafford, Grace A / Bechtold, Lesley / Grammer, Amrie C / Lipsky, Peter E / Roopenian, Derry C / Chang, Chih-Hao

iScience

2023 Volume 26, Issue 9, Page(s) 107487

Abstract: Aberrant metabolic demand is observed in immune/inflammatory disorders, yet the role in pathogenesis remains unclear. Here, we discover that in lupus, activated B cells, including germinal center B (GCB) cells, have remarkably high glycolytic requirement ...

Abstract	Aberrant metabolic demand is observed in immune/inflammatory disorders, yet the role in pathogenesis remains unclear. Here, we discover that in lupus, activated B cells, including germinal center B (GCB) cells, have remarkably high glycolytic requirement for survival over T cell populations, as demonstrated by increased metabolic activity in lupus-activated B cells compared to immunization-induced cells. The augmented reliance on glucose oxidation makes GCB cells vulnerable to mitochondrial ROS-induced oxidative stress and apoptosis. Short-term glycolysis inhibition selectively reduces pathogenic activated B in lupus-prone mice, extending their lifespan, without affecting T follicular helper cells. Particularly, BCMA-expressing GCB cells rely heavily on glucose oxidation. Depleting BCMA-expressing activated B cells with APRIL-based CAR-T cells significantly prolongs the lifespan of mice with severe autoimmune disease. These results reveal that glycolysis-dependent activated B and GCB cells, especially those expressing BCMA, are potentially key lupus mediators, and could be targeted to improve disease outcomes.
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107487
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice.

Wells, Ann E / Wilson, John J / Sears, John D / Wei, Jian / Heuer, Sarah / Pandey, Raghav / Costa, Mauro W / Kaczorowski, Catherine C / Roopenian, Derry C / Chang, Chih-Hao / Carter, Gregory W

bioRxiv : the preprint server for biology

2023

Abstract	Objective: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. Methods: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. Results: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. Conclusions: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.24.537717
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Functional analysis of Collagen 17a1: A genetic modifier of junctional epidermolysis bullosa in mice.

Sproule, Thomas J / Wilpan, Robert Y / Low, Benjamin E / Silva, Kathleen A / Reyon, Deepak / Joung, J Keith / Wiles, Michael V / Roopenian, Derry C / Sundberg, John P

PloS one

2023 Volume 18, Issue 10, Page(s) e0292456

Abstract: Previous work strongly implicated Collagen 17a1 (Col17a1) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation (Lamc2jeb) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was ... ...

Abstract	Previous work strongly implicated Collagen 17a1 (Col17a1) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation (Lamc2jeb) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2-3 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S/G and 1277 N/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of Lamc2jeb/jeb JEB. Together these studies exploiting gene editing to functionally dissect the Col17a1 modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous 'healthy' alleles in other genes.
MeSH term(s)	Animals ; Mice ; Epidermolysis Bullosa, Junctional/genetics ; Non-Fibrillar Collagens/genetics ; Non-Fibrillar Collagens/metabolism ; Collagen/genetics ; Mutation ; Amino Acids/genetics
Chemical Substances	Non-Fibrillar Collagens ; Collagen (9007-34-5) ; Amino Acids
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0292456
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorum.

Sproule, Thomas J / Wilpan, Robert Y / Wilson, John J / Low, Benjamin E / Kabata, Yudai / Ushiki, Tatsuo / Abe, Riichiro / Wiles, Michael V / Roopenian, Derry C / Sundberg, John P

PloS one

2023 Volume 18, Issue 10, Page(s) e0293218

Abstract: The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong ... ...

Abstract	The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong candidate genes including dystonin (Dst/Bpag1). Here, CRISPR/Cas9 was used to alter exon 23 in mouse skin specific isoform Dst-e (Ensembl GRCm38 transcript name Dst-213, transcript ID ENSMUST00000183302.5, protein size 2639AA) and validate a proposed arginine/glutamine difference at amino acid p1226 in B6 versus 129 mice as a modifier of EB. Frame shift deletions (FSD) in mouse Dst-e exon 23 (Dst-eFSD/FSD) were also identified that cause mice carrying wild-type Lamc2 to develop a phenotype similar to human EB simplex without dystonia musculorum. When combined, Dst-eFSD/FSD modifies Lamc2jeb/jeb (FSD+jeb) induced disease in unexpected ways implicating an altered balance between DST-e (BPAG1e) and a rarely reported rodless DST-eS (BPAG1eS) in epithelium as a possible mechanism. Further, FSD+jeb mice with pinnae removed are found to provide a test bed for studying internal epithelium EB disease and treatment without severe skin disease as a limiting factor while also revealing and accelerating significant nasopharynx symptoms present but not previously noted in Lamc2jeb/jeb mice.
MeSH term(s)	Animals ; Mice ; Dystonia/genetics ; Dystonia/metabolism ; Dystonic Disorders/metabolism ; Dystonin/metabolism ; Epidermolysis Bullosa/genetics ; Epidermolysis Bullosa Simplex/diagnosis ; Epidermolysis Bullosa Simplex/genetics ; Epidermolysis Bullosa Simplex/metabolism ; Epidermolysis Bullosa, Junctional/genetics ; Epidermolysis Bullosa, Junctional/diagnosis ; Epidermolysis Bullosa, Junctional/metabolism ; Skin/metabolism
Chemical Substances	Dystonin ; Dst protein, mouse
Language	English
Publishing date	2023-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0293218
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Functional analysis of Collagen 17a1

Thomas J Sproule / Robert Y Wilpan / Benjamin E Low / Kathleen A Silva / Deepak Reyon / J Keith Joung / Michael V Wiles / Derry C Roopenian / John P Sundberg

PLoS ONE, Vol 18, Iss 10, p e

A genetic modifier of junctional epidermolysis bullosa in mice.

2023 Volume 0292456

Abstract	Previous work strongly implicated Collagen 17a1 (Col17a1) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation (Lamc2jeb) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2-3 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S/G and 1277 N/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of Lamc2jeb/jeb JEB. Together these studies exploiting gene editing to functionally dissect the Col17a1 modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous 'healthy' alleles in other genes.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorum.

Thomas J Sproule / Robert Y Wilpan / John J Wilson / Benjamin E Low / Yudai Kabata / Tatsuo Ushiki / Riichiro Abe / Michael V Wiles / Derry C Roopenian / John P Sundberg

PLoS ONE, Vol 18, Iss 10, p e

2023 Volume 0293218

Abstract	The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong candidate genes including dystonin (Dst/Bpag1). Here, CRISPR/Cas9 was used to alter exon 23 in mouse skin specific isoform Dst-e (Ensembl GRCm38 transcript name Dst-213, transcript ID ENSMUST00000183302.5, protein size 2639AA) and validate a proposed arginine/glutamine difference at amino acid p1226 in B6 versus 129 mice as a modifier of EB. Frame shift deletions (FSD) in mouse Dst-e exon 23 (Dst-eFSD/FSD) were also identified that cause mice carrying wild-type Lamc2 to develop a phenotype similar to human EB simplex without dystonia musculorum. When combined, Dst-eFSD/FSD modifies Lamc2jeb/jeb (FSD+jeb) induced disease in unexpected ways implicating an altered balance between DST-e (BPAG1e) and a rarely reported rodless DST-eS (BPAG1eS) in epithelium as a possible mechanism. Further, FSD+jeb mice with pinnae removed are found to provide a test bed for studying internal epithelium EB disease and treatment without severe skin disease as a limiting factor while also revealing and accelerating significant nasopharynx symptoms present but not previously noted in Lamc2jeb/jeb mice.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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